TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a co-inhibitory receptor protein also known as WUCAM, Vstm3 or Vsig9. TIGIT was discovered in genomic searches for proteins specifically expressed on T cells, and has an immunoglobulin variable domain, a transmembrane domain, and an immunoreceptor tyrosine-based inhibitory motif (ITIM), and contains signature sequence elements of the PVR protein family. It is known to interact with poliovirus receptor (PVR; CD155) and with nectin2 (CD112). See e.g. Stengel et al. (2012) Proc. Nat'l Acad. Sci. (USA) 19:5399; WO 2006/124667; WO 2009/126688. Although PVR may interact with the co-activating receptor DNAM-1 (CD226) to enhance tumor killing, the high affinity TIGIT/PVR interaction would inhibit such killing, and may act to prevent killing of normal (self) cells that also express PVR. Stanietsky et al. (2009) Proc. Nat'l Acad. Sci. (USA) 106:17858. The dominance of this inhibitory interaction may be important in suppression of anti-self immune reactions, but in the tumor context it suppresses tumor eradication. Id.
TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Yu et al. (2009) Nat. Immunol. 10:48. TIGIT and other such co-inhibitory molecules (e.g. CTLA-4, PD-1, Lag3 and BTLA) may play a role in evasion of immunosurveillance by tumor cells. Experiments have shown that PVR/CD155 is over-expressed on melanoma cells (Inozume et al. (2014) J. Invest. Dermatol. 134:S121—Abstract 693) and various other tumors. It is possible that the TIGIT/PVR interaction can shield such tumor cells from immune-mediated eradication by inhibiting anti-tumor responses of T and NK cells. Stanietsky et al. (2009) Proc. Nat'l Acad. Sci. (USA) 106:17858 and Lozano et al. (2012) J. Immunol. 188:3869. Other experiments have identified a TIGIT subset of regulatory T cells (Tregs) that selectively suppress Th1 and Th17 responses (Joller et al. (2014) Immunity 40:569), suggesting an alternative mechanism by which an anti-TIGIT antibody may enhance anti-tumor immune response.
TIGIT may act to “turn off” the immune response similarly to other co-inhibitory receptors such as CTLA-4, PD-1 and BTLA. Id. Antibodies targeting CTLA-4 (ipilimumab) and PD-1 (nivolumab, pembrolizumab) have been approved for the treatment of human cancers, validating this therapeutic approach. Antibodies that bind to human TIGIT might also find use in treatment of cancers. See e.g. WO 2006/124667. In mouse models, antibody blockade of both PD-L1 and TIGIT leads to a synergistic enhancement of CD8+ T cell mediated tumor rejection. Grogan et al. (2014) J. Immunol. 192(1) Suppl. 203.15; Johnston et al. (2014) Cancer Cell 26:1-15. Similar results have been obtained in animal models of melanoma. Inozume et al. (2014) J. Invest. Dermatol. 134:S121—Abstract 693. Some experiments suggest that TIGIT blockade is effective to enhance anti-tumor CD8+ T cell response only in the presence of the co-activating receptor DNAM-1/CD226, which competes with TIGIT for binding to PVR/CD155. Johnston et al. (2014) Cancer Cell 26:1-15.
Recent experiments have demonstrated that intratumoral bacteria expressing Fap2 protein may inhibit NK cell mediated tumor killing by binding to TIGIT (Gur et al. (2015) Immunity 42:344), suggesting that eliminating such bacteria, blocking the interaction of TIGIT with Fap2, or blocking the activity of TIGIT generally, may be useful in treatment of cancer, e.g. colorectal cancer. Hampton (2015) AMA 313:1305.
The need exists for improved methods of treating cancer and chronic viral infections and medicaments, such as therapeutic monoclonal antibodies, for use in the methods. Medicines for use in such improved methods of treatment may comprise antibodies or antibody fragments that specifically bind to TIGIT and reverse or partially reverse the TIGIT-mediated suppression of anti-tumor or anti-viral immune responses.